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Thursday, October 18, 2012

Questions for Celsion Management During Upcoming Q3 CC

[NOTE: LIST WILL BE UPDATED AS CC APPROACHES] As per usual, I have a laundry list of questions for Celsion management during the upcoming conference call (likely mid-Nov, tbd for now). Especially since this will likely be the last time we hear management until the much anticipated top-line results from the HEAT study are announced, I pulled out all the stops in terms of questions for the company. Many of these are very "forward-looking" if you will, and are only relevant if ThermoDox succeeds (who cares if patients were treated on an outpatient basis versus inpatient if the study fails, right?), at the same time, these are geared towards getting investors thinking about the challenges that may come down the road from a competitive/marketing perspective assuming ThermoDox passes this critical upcoming test.

Has 380 PFS events been confirmed, triggering data analysis?

Can we still expect DATA by end of the year?

***[NEWLY ADDED] There is a clear consensus amongst journalists and analysts that a successful HEAT trial will immediately march the stock upwards to the $500M+ mkt cap range. Why do you think that despite being a late stage oncology company with a 1st line therapy for one of the largest unaddressed cancers, Wall Street places such a low valuation on the company? Does the company have any comments on this?

Without speculating about the treatment arm, how surprised would the company be, especially given the firm and repeated stance of a 12 month estimate for the control arm, if the control arm came in 50% greater than the 12 month estimate the company provided, or 18 months? Given that control arms of clinical trials can, and often do, outperform "historical controls", how likely is this in the HEAT study, particularly when the focus is around a procedure in RFA that is highly influenced by operator skill and experience?

***We know that the HEAT trial sites are some of the best and most reputable sites in the world with significant experience with RFA. For this same reason, is it fair to say that a real possibility exists for the control arm to significantly outperform the 12 month PFS guidance the company has provided? If not, why?

Can we assume that most HEAT patients are in the 3-5cm cohort? What proportion of patients roughly are in each cohort?

I read in an analyst report that 90% of patients in the HEAT trial are Child-Pugh A, can you confirm this? Clearly, there is a big difference in outcomes between A versus B patients.

Can you tell us how many RFA treatments a typical patient has received in the HEAT study, approximately? As you know, every analystcovering the stock has assumed only 1 RFA treatment per patient, which we know with certainty fails to accurately reflect the number of RFA treatments patients receive throughout their overall HCC treatment.

On your RCW poster presented at ESMO, the company highlighted what I like to call a "logistical" challenge for getting the timing of ThermoDox aligned with hyperthermia treatment, specifically, "infusion of cytotoxic agent in chemotherapy suite followed by transfer to radiologic oncology to administer hyperthermia." How has this noted challenge played out in the HEAT study specifically, and how do you expect this to play out in the real world? What implications does this have for how the company educates and targets future customers?

[NEWLY ADDED] The company clearly made some assumptions when designing the HEAT study, such as the hypothesized effect ThermoDox would have in reducing local and intrahepatic distant spread. What assumptions did the company make in terms of ThermoDox' ability to reduce intrahepatic distant spread, both within the same liver segment, and in other liver segments? As an aside, I personally expect ThermoDox to reduce at least 80% of "true" local progression, but struggle in assigning a number in terms of hypothesized reduction in intrahepatic distant spread. Again, and again as I have stated, this will make all the difference in the world in terms of yielding great results versus spectacular results when it comes to PFS in particular.

***Just to confirm, were most patients treated in an outpatient versus inpatient setting? Within outpatient treated patients, what was the distribution between physician offices versus hospital outpatient settings? What percentage of patients, if any, in the HEAT study required any sort of post-treatment observation?

***[NEWLY ADDED]Can you comment on the average number of RFA treatments (factoring in those who will need additional RFA for technical success within the first month as well as downstream post-progression RFA treatments) a typical patient has received in the HEAT study right up until they no longer are eligible for RFA? Some clarity on this would be greatly appreciated, as you know, most analysts are assuming one, single, treatment per patient, which from my understanding, grossly underestimates the number of RFAs a typical patient receives as part of their treatment for HCC. Perhaps even more importantly, this significantly underestimates the revenue estimates analysts are placing on ThermoDox.

[NEWLY ADDED] It is a given that the ThermoDox arm, by definition, will have more adverse events than the RFA-only arm, as a function of the known side-effect profile of doxorubicin. Clearly given all the DMC reviews, these side-effects have been managed appropriately and are relatively minor. That being said, does the company expect any challenges/pushback from clinicians in the real-world with respect to managing side-effects for this population following RFA/ThermoDox?

***[NEWLY ADDED] If the HEAT study comes close, but ultimately, fails to hit its PFS endpoint in January, would the company still make a case to seek approval? In that scenario, how important does the yet to be mature OS become?

***Let's assume ThermoDox is on the market. If I am a physician about to treat a patient with a 7 cm lesion not amenable to transplantation or resection, tell me exactly why I should use RFA plus ThermoDox as opposed to doxorubicin eluting beads (DEB)-TACE followed by RFA alone? What is the specific point of differentiation here? (to answer my own question for starters, TACE is another cumbersome procedure)

What do you expect the bridging study in Japan to look like from a trial design perspective? The company said differences in "SOC" lead to the decision to halt enrollment. Well, what differences in SOC will be reflected in this new bridging study?

What would success in the HEAT study mean in terms of potential success in the ongoing ABLATE study? In that context, how does the local progression only primary endpoint in the ABLATE trial affect that trial's chances for success?

At the FUS foundation 3rd symposium, some data was presented around a novel thermosensitive liposome with some suggested improvements over Celsion's LTSL in terms of serum stability. Elsewhere, we have seen some data for a "HaT" liposome with apparently much greater serum stability than ThermoDox and improved release dynamics (more than happy to send you the papers). Granted, these products are several years away from clinical application, nowhere near ThermoDox, but how does the company view these newer thermosensitive liposomes? By the same token, do these products present opportunities for the company in terms of next steps for clinical development?

I intend to send all of these to management personally ahead of the call [Already sent earlier draft to management, resent updated list 11/11/2012]. Again, many of these questions are simply not important for the task at hand: making sure ThermoDox hits its PFS endpoint. That is really all that matters here. But, nevertheless, I want these items to stay top of mind for investors/management.

5 comments:

In 9 and 12, you mention some other therapy. If relevant, could you also make reference to the percutaneous RFA in your questions, since it seems to give excellent results? (http://emedicine.medscape.com/article/1390475-overview) Why Thermodox would be more appropriate and would give better results?

Appreciate the comments. You might have a couple concepts mixed up. So RFA plus ThermoDox is the treatment arm versus RFA alone. RFA can be done in 3 ways, open surgical, laparoscopic, or percutaneously. Percutaneous is most commonly done, and most patients in the HEAT study (80% plus) received percutaneous RFA.

I think your question might simply be, what if percutaneous RFA by itself is doing very well? Yep, that is one theory, and that ties back to question 2. I don't think that is the case, I FIRMLY think the control arm will not come in a hair over 16 months maximum.

Engawyer, sorry for the late response. As far as I know, the company's work force has not changed significantly in the recent months, but I have no idea to what extent they may have engaged outside consultancies. I see what you are getting at though (if they are hiring they might be planning for success), but I am not sure that we could conclude that either way.

As to your Q2, perhaps I am a bit unclear as to the question. The company can't get any additional patent protections on their drug based on the trial site by trial site variation in how they provide RFA, which mind you, is relatively standard in many ways across the trial.

Sia, I imagine there will be discoveries made as to which sites performed better. From that Celsion will be able to investigate whether the variation in performance could be attributed to any step or condition unique tot he site(s). This key discovery would be patentable and applicable to all similarly administered treatments.

An additional question -the way I read the PR, the DIGNITY results indicated a safety profile consistent with regular chemo. This is incorrect correct? I am assuming that patient responses were far better than they would have been had a large dosage of dox sufficient to achieve the concentrations achieved by Tdox at the breast wall was administered. Hence, the utility of Tdox. Could they please clarify.